Objectives: a. The total project. This grant is designed to uncover new secondary metabolites from higher plants which have novel chemical structures and which have potential for clinical use as antibiotics in treating infections caused by microorganisms against which current fermentation based antibiotics are unsatisfactory in some significant way. Central to this effort is the use of rational modern testing methods and we have chosen to search among the higher plants for these structurally and therapeutically novel agents. Once confirmed to be active the most potent plant extracts are fractionated in order to isolate the active constituents in pure form. These products are then evaluated for their antimicrobial spectrum and comparative potency in vitro in comparison with established antibiotics. In vivo evaluation in infected mice is carried out on the most potent agents. It is anticipated that the agents uncovered will be new to the antibiotic literature so structure determination is required. Suitable agents will be synthesized with a view to exploring the relationship between structure and bioactivity in the hope of improving the medicinal potential of the active substances. The diseases under attack include tuberculosis, infections due to Gram-negative bacteria, and fungal diseases. Bibliographic references: 1) L.A. Mitscher, M. Shipchandler, H.D.H. Showalter and M.S. Bathala, Antimicrobial Agents from Higher Plants, Synthesis in the Canthin-6-one (6H-Indolo(3,2,1-de)(1,5)- Naphthyridin-6-one Series, Heterocycles, 3, 7(1975). 2) C.R. Chen, J.L. Beal, R.M. Doskotch, L.A. Mitscher and G.H. Svoboda, A Phytochemical Study of Doryphora sassafras. II. Isolation of Eleven Crystalline Alkaloids from the Bark, Lloydia, 37, 493(1974).